Clinical Note

In certain clinical situations, such as congestive heart failure or liver failure, fluid reabsorption by the proximal tubule is excessive. In these settings, the proximal tubule may reabsorb up to 90% of the filtered load of salt and water so that diuretics that act on segments that are more distal may have relatively little effect. Therefore, one must interfere with the proximal reabsorptive process to effect a diuresis and natriuresis and rid the body of excess extracellular fluid volume.

Decreasing proximal reabsorption could be attempted by using a carbonic anhydrase inhibitor such as acetazolamide, which reduces proximal HCO3 reabsorption by slowing down the dehydration of carbonic acid to CO2 and water, but carbonic anhydrase inhibitors are relatively weak diuretics and produce a metabolic acidosis as a side effect of their interference with HCO3 reabsorption. The solution is to use a freely filtered but poorly reabsorbed solute. A useful substance for this purpose is mannitol, a monosaccharide not normally found in mammals. It has a molecular weight of 182 Da so that it is freely filtered at the glomerulus, but it has a poor ability to permeate the proximal tubule epithelium due to its size and polarity, and the absence of specialized transporters for its reabsorption. Mannitol is also fairly water soluble [solutions of 25 g/dL (1400 mmol/L) are prepared for intravenous administration], so that infusion of a small volume can produce a high plasma mannitol concentration. Let us consider quantitatively what would happen along the nephron after the infusion of a typical diuretic dose of mannitol. The following numerical example illustrates not only the effects of an osmotic diuretic but gives some insight into the mechanism of isosmotic volume reabsorption and the rates of salt and water delivery to the distal nephron.

Numerical Example of Osmotic Diuresis Produced by Mannitol

Consider first the normal rates of salt and water reabsorption in the proximal tubule. Normal plasma osmolality is 290 mOsm/kg H2O, which is primarily due to Na+ present at a concentration of 140 mmol/L with its associated anions. With a normal GFR of 130 mL/min, the rate of Na+ filtration would be (0.13 • 140) = 18.2 mmol/min. By the end of the proximal tubule, two-thirds of the filtered fluid has been reabsorbed, leaving a flow rate of (0.333 • 130) = 43.3 mL/min, containing approximately the same Na+ concentration as the plasma so that the delivery of Na+ to the loop of Henle would be (0.0433 • 140) = 6.1 mmol/min. The rate of proximal reabsorption is the difference between the rate of filtration and the rate of delivery to the loop of Henle. For water, the reabsorption rate is (130 - 43.3) = 86.7 mL/min. For Na+ the reabsorption rate is (18.2 - 6.1) = 12.1 mmol/min.

Consider now the consequences of giving an intravenous infusion of hypertonic mannitol sufficient to produce a plasma mannitol concentration of 30 mmol/L, which would give a plasma osmolality of 320 mOsm/kg H2O, a typical increase in clinical practice. For convenience, we assume that the plasma Na+ concentration remains the same. Note that there would be an equivalent increase in the osmolality of the intracellular fluid, even though mannitol would not enter the cells to any appreciable extent. Owing to the high water permeability of most cell membranes, water leaves the cells rapidly until intra- and extracellular osmolality are equal. Thus, the movement of water would expand the extracellular space at the expense of the intracellular fluid compartment.

Assuming the GFR also remains constant, the rate of Na+ filtration would still be 18.2 mmol/ min. The rate of mannitol filtration would be (0.13 • 30) = 3.9 mmol/min. At the end of the proximal tubule, because of the osmotic effect of the mannitol, which is only poorly reabsorbed passively, assume that only 58% of the filtered water has been reabsorbed so that the flow rate is now (0.42 • 130) = 54.6 mL/min. Assume that only 5% of the filtered mannitol has been reabsorbed so that its concentration has risen to (3.9 • 0.95/.0546) = 67.9 mmol/L. Because the water permeability of the proximal tubule is very high, the tubular fluid always has nearly the same osmolality as the plasma, which in this case is 320 mOsm/kg H2O. However, if the mannitol concentration is about 68 mmol/L, the remainder of the osmolality of the tubular fluid that is not due to mannitol would be (320 - 68) = 252 mOsm/kg H2O. If Na+ makes up approximately one-half of this osmolality, the Na+ concentration at the end of the proximal tubule would be 126 mmol/L, and its delivery to the loop of Henle would be (0.0546 • 126) = 6.9 mmol/min. [It is important to note that, even though the Na+ concentration of the tubular fluid is much less than in normal circumstances, the Na+ delivery to the loop of Henle is still increased by (6.9 - 6.1) = 0.8 mmol/min because of the increased flow rate!] The rate of volume reabsorption in the proximal tubule is (130 - 54.6) = 75.4 mL/min, and the rate of Na+ reabsorption is (18.2 - 6.9) =11.3 mmol/ min. This illustrates that the reabsorption of both water and Na+ are decreased because of the osmotic diuresis created by mannitol.

down its electrochemical potential gradient into the proximal tubule epithelial cells and is pumped out of the cells across their basolateral membrane into the interstitial space (see Fig. 2). The movement of Na+ into the cells represents the loss of a considerable amount of potential energy. By coupling this downhill movement to the uphill transport of sugars, amino acids, and other solutes into the cells, the proximal tubule realizes a considerable energy savings. It requires no more energy investment than that already obligated for the Na+,K+-ATPase to transport Na+ out of the cell.

The energy available from downhill luminal Na+ entry is coupled to the transport of several organic solutes by specific membrane transporters that simultaneously transport the solute plus Na+ across the membrane. This process is referred to as cotransport or symport. The transcellular movement of the cotrans-ported solute is shown in Fig. 12. The solute enters across the luminal membrane against a concentration gradient, driven by the energy available from the cotransport of Na+ down its electrochemical potential gradient. Owing to the higher concentration of the

FIGURE 12 Active reabsorption of organic solutes by cotransport with Na+. The active transport of many organic solutes (S) from the lumen into the proximal tubule cell is driven by cotransport with Na+ on specific carrier molecules. The Na+ moves into the cell down its electrochemical potential gradient, thus making energy available to concentrate S in the cell. The potential energy for Na+ entry is maintained by the operation of the Na+,K+-ATPase in the basolateral membrane. The basolateral membrane contains a facilitated diffusion mechanism that allows S to diffuse out of the cell down its electrochemical potential gradient into the interstitial fluid and the plasma in the peritubular capillary network.

FIGURE 12 Active reabsorption of organic solutes by cotransport with Na+. The active transport of many organic solutes (S) from the lumen into the proximal tubule cell is driven by cotransport with Na+ on specific carrier molecules. The Na+ moves into the cell down its electrochemical potential gradient, thus making energy available to concentrate S in the cell. The potential energy for Na+ entry is maintained by the operation of the Na+,K+-ATPase in the basolateral membrane. The basolateral membrane contains a facilitated diffusion mechanism that allows S to diffuse out of the cell down its electrochemical potential gradient into the interstitial fluid and the plasma in the peritubular capillary network.

solute in the cell, there is a concentration gradient favoring its movement out of the cell. Other transport proteins facilitate passive solute exit across the baso-lateral membrane. These facilitated diffusion mechanisms allow the solute to move readily across the cell membrane to the interstitial space.

Glucose

All useful organic substrates are reabsorbed by Na+ cotransport mechanisms. These include glucose, amino acids, lactate, acetate, citrate, succinate, oxalate, and various carboxylic acids. However, the carriers involved in a given cotransport process are limited in number, so there is a maximal rate of transport for each of these substrates based on the number of transporters available in the proximal tubule. The effect of this limitation on the overall renal handling of these solutes is best illustrated by glucose. As shown in Fig. 13, at plasma concentrations of glucose up to double the normal ~100 mg/dL, there is no glucose in the urine. (Actually, there are normally trace amounts that are not detected by the usual clinical laboratory methods.) In other words, for all practical purposes, 100% of the filtered glucose load is reabsorbed. However, when the plasma glucose concentration exceeds 200-220 mg/dL, readily detectable amounts of glucose appear in the urine.

The plasma glucose concentration at which glucose begins to appear in the urine is called the renal plasma glucose threshold. Above the threshold, the rate of excretion increases until it parallels the rate of filtration. The rate of glucose reabsorption can be calculated as the rate of filtration minus the rate of excretion, and as the plasma glucose concentration rises above about 350 mg/dL, the rate of reabsorption reaches a maximum of about 375 mg/min. This maximum, which is referred to as the transport maximum (Tm), is reached when all nephrons are reabsorbing glucose at their maximal rate and any additional amount filtered is excreted. The maximal rate of transport is a function of the total transport capacity of each transporter and their number. Because the number is proportional to the number of functioning nephrons, the Tm for glucose decreases in acute or chronic renal failure in proportion to the decrease in the number of functioning nephrons. However, the renal plasma glucose threshold remains relatively constant.

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